A facile and regioselective synthesis of 2,5-disubstituted pyrroles via gold-catalyzed cycloisomerization of acetylenylaziridines

Article abstract of DOI:10.1016/j.tetlet.2009.05.091

Gold-catalyzed cycloisomerization reaction of acetylenylaziridines provides 2,5-disubstituted pyrroles in high yields. The presence of protic species accelerates the reaction rate and improves the yields of pyrrole products.

Full text of DOI:10.1016/j.tetlet.2009.05.091

Tetrahedron Letters 50 (2009) 6944–6946
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Tetrahedron Letters
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A facile and regioselective synthesis of 2,5-disubstituted pyrroles
via gold-catalyzed cycloisomerization of acetylenylaziridines
*
Dong-Dong Chen, Xue-Long Hou , Li-Xin Dai
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Gold-catalyzed cycloisomerization reaction of acetylenylaziridines provides 2,5-disubstituted pyrroles in
high yields. The presence of protic species accelerates the reaction rate and improves the yields of pyrrole
products.
Received 13 May 2009
Revised 14 May 2009
Accepted 15 May 2009
Available online 28 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Transition-metal-catalyzed cyclizations and cycloisomerization
reactions of enynes have so far been a convenient protocol to ren-
der a variety of functionalized ring structures.1 Among them the
gold catalysts have demonstrated their unique catalytic activities
through the activation of alkynes, emerging as the powerful cata-
lyst for this rapidly developing research area in past few years.2
The transformations of epoxides3 and cyclopropanes4 containing
carbon–carbon triple bond to furans, polycyclic ring systems and
other functionalized compounds in the presence of gold com-
pounds as catalyst have been reported. However, few reports were
given on the gold-catalyzed transformation of aziridines in spite of
the fact that the metal-catalyzed conversions of aziridines have
well been documented.5 We have developed several simple proce-
dures for the synthesis of functionalized aziridines including acet-
ylenylaziridines.6 We envisage that such triple bond in
acetylenylaziridines could be activated by gold compounds and
the pyrrole formation7 seems to be feasible via intramolecular at-
tack of nitrogen of the aziridine towards gold(I)-activated triple
bond. Herein, we present a new synthetic approach to 2,5-disubsti-
tuted pyrroles utilizing the acetylenylaziridines in the presence of
Au catalyst.8
was added (entries 11, 12, 14 and 15).12 The presence of protic spe-
cies plays an important role. Good yield of 2a was provided if
0.1 mL of MeOH was added to the reaction system (entries 14
and 15) while lower yield of 2a was furnished without the use of
MeOH (entry 11).13 It is noticeable that removing trace amount
of water from the system with 4 Å MS prohibited this reaction (en-
try 13). The reaction still proceeded smoothly if the catalyst load-
ing decreased to 5 mol %, providing 60% yield of 2a in 17 h (entry
15).
Ts
N
catalyst (10 mol %)
Ph
Ph
ð1Þ
N
Ph
THF, r.t.
Ts
Ph
1a
2a
Then we investigated the influence of solvents on these isomer-
izations (Eq. 2, Table 2). We found that the pyrrole 2a was afforded
efficiently if the reaction ran in toluene, DCM and THF (entries 1–
3), among them THF was a better choice, while poor results were
provided if CH3CN and CH3OH were used as solvents (entries 4
and 5).
PPh3AuCl (10 mol %)
AgOTf (10 mol %)
Ts
N
The choice of catalyst to activate the nitrogen of aziridine with
low nucleophilicity is vital,7a,9 although it was easy with which the
alkynyloxiranes were isomerized to furan with gold(III) chloride as
a catalyst via the attack of oxygen of epoxide as a nucleophile to
the activated triple bond.10 Thus, different metal salts and com-
plexes were screened by using aziridine 1a for our initial investiga-
tion (Eq. 1, Table 1). In the presence of 10 mol % of transition-metal
complexes IPrCuCl and Ru(PPh3)2Cl2 or metal salts Y(OTf)3, In(-
Ph
Ph
ð2Þ
solvent/MeOH, r.t.
Ph
N
Ts
Ph
2a
1a
With the optimized conditions in hand, we have probed the
scope of this isomerization reaction (Eq. 3, Table 3). Varying the
aryl and alkyl substituents at either aziridines ring or the terminal
carbon of triple bond had a little influence on the yield of the reac-
tion, all reactions proceeded smoothly at room temperature and
were completed within 10 h to afford 2,5-disubstituted pyrroles
in high yields, except that of aziridine 1j with Phenyl and acetyle-
nyl group in 19 h (entry 10). High yields (87–99%) of pyrroles 2
were furnished when one substituent or two substituents on the
aziridines ring and the terminal carbon of triple bond were alkyl
(entries 4–8 and 13–14) while the yields were a little bit lower
11
OTf)3, PtCl2 and AgOTf, the formation of pyrrole 2a was not ob-
served (entries 1–6). However, a few percentage of pyrrole 2a
was detected when Au compounds were used (entries 7, 8 and
10). The yield of 2a increased dramatically when 10 mol % of AgOTf
* Corresponding author.
E-mail address: xlhou@mail.sioc.ac.cn (X.-L. Hou).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.091

D.-D. Chen et al. / Tetrahedron Letters 50 (2009) 6944–6946
6945
Table 1
Screening of metal catalysts in the cycloisomerization of aziridine 1aa
Ts
N
Ts
R1
N
LAu
Yieldb (%)
R2
R1
Entry
Catalyst
Time (h)
1
R2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
IPrCuCl
Y(OTf)3
In(OTf)3
PtCl2
Ru(PPh3)2Cl2
AgOTf
48
48
48
16
24
16
96
72
48
48
36
4
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
8
<5
N.R.
<5
58
50
N.R.
69
60
2
AuL
R2
LAu
R2
R1
R1
N
Ts
B
N
Ts
NaAuCl2ꢀH2O
AuCl3
AuL
R2
c
PicAuCl2
PPh3AuCl
-H
PPh3AuCl/AgOTf
AuCl3/AgOTf
R1
N
Ts
PPh3AuCl/AgOTfd
PPh3AuCl/AgOTfe
PPh3AuCl/AgOTff
20
9
17
A
Scheme 1. Mechanistic hypothesis for the cycloisomerization of aziridines.
a
Reactions were conducted with
a solution of 1a (74.7 mg, 0.2 mmol) and
10 mol % catalyst (0.5 mL 0.04 M AgOTf–THF solution was used if necessary) in THF
(0.2 M) protected from light at rt.
b
R3
N
PPh3AuCl (10 mol %)
AgOTf (10 mol %)
Isolated yield.
Pic = pyridine-2-carboxylato.
4 Å MS was added.
MeOH (0.1 mL) was added.
c
d
R2
R1
ð3Þ
N
R1
e
THF/MeOH (10/1) r.t.
R2
R3
f
5 mol % catalyst was used with MeOH (0.1 mL).
1
2
The reaction seems to be like that reported in the literature by
Hashmi and Sinha10 to proceed via the gold(I)-activation of alkyne
followed by cycloisomerization to produce intermediate A, depro-
tonation of it affords intermediate B, which is converted to pyrrole
immediately via the deprotonation and regenerates Au catalyst
(Scheme 1).
To study the reaction mechanism, the deuterium exchange
experiments were carried out (Eq. 4). Moderate proportion of
deuterated product 2n observed with deuterium-labelled meth-
anol suggests that the proton sources are supplied not only
from methanol but also from the proton released from the
intermediate A (Scheme 1). A similar deuteration was also ob-
served when the reaction proceeded in either polar or apolar
solvent (Eq. 4). The fast intramolecular protonation process is
supported further by the fact that we failed to trap the inter-
mediate B with different electrophiles. These results suggest
that gold(I)-activation of alkyne cycloisomerization might be
the rate-determining step.
Table 2
Influence of different solvents on the cycloisomerization of aziridine 1aa
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
THF
Toluene
DCM
CH3CN
CH3OH
9
4
4
6
6
69
63
67
N.R.
Complex
a
Reactions were carried out as follows: 1a (74.7 mg, 0.2 mmol) and PPh3AuCl
(10 mg, 0.02 mmol) with AgOTf–THF solution (0.5 mL, 0.04 M, 0.02 mmol) in sol-
vent (0.5 mL) and MeOH (0.1 mL) protected from light at rt.
b
Isolated yield.
Table 3
Scope of gold(I)-catalyzed cycloisomerization of aziridines 1a
Substrate 1
Time (h)
Yieldb (%)
Entry
R1
R2
R3
PPh3AuCl (10 mol %)
(H)D
Ts
AgOTf (10 mol %)
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
TMS
TMS
H
Ts
Ts
Ts
Ts
Ts
Ts
Ms
Ts
Ts
Ts
Ts
Ts
Ts
Ts
9
6
2
5
6
3
10
3
12
19
3
69 (2a)
86 (2b)
74 (2c)
95 (2d)
94 (2e)
99 (2f)
76 (2g)
95 (2h)c
70 (2i)c
59 (2i)
94 (2k)
71 (2l)
94 (2m)
87 (2n)
solvent/CD3OD (10/1)
N
o-ClC6H5
1-Nap
i-Pr
Cy
n-Pr
Ph
Cy
Ph
Ph
Ph
O
r.t.
O
ð4Þ
Ts
1n
2n
THF, 5h: 80% yield, D/H = 1.8/1
toluene, 14h: 79% yield, D/H = 2.3/1
In summary, we have developed a new and simple pathway to
form 2, 5-disubstitute pyrroles in high yields with gold(I)-cata-
lyzed efficient cycloisomerization of acetylenylaziridines. The pres-
ence of protic species accelerates the reaction rate and improves
the yields of pyrrole products. Further studies on the acetylenylaz-
iridines transformations using Au catalyst and the applications in
organic synthesis are underway.
c-Prd
n-Bu
n-Bu
CH2OCH3
1-Nap
Cy
Cy
2
4
3
a
Reactions were carried out as follows: 1 (0.2 mmol) and PPh3AuCl (10 mg,
0.02 mmol) with AgOTf–THF solution (0.5 mL, 0.04 M, 0.02 mmol) in mixed sol-
vents of THF/MeOH = 5/1 (0.6 mL) protected from light at rt.
b
Isolated yield.
R2 = H in the product.
c-Pr = cyclopropyl.
c
Acknowledgements
d
Financial support from the National Natural Science Foundation
of China (20532050, 20672130, 20821002), the Major Basic Re-
search Development Programme (2006CB806100), Chinese Acad-
emy of Sciences and Science and Technology Commission of
Shanghai Municipality is acknowledged.
(59–74%) if both substituents are aryl (entries 1, 3 and 7) or aryl
and TMS or H (entries 9 and 10) with the exception of the reaction
of 1b and 1l (entries 2 and 12).

6946
D.-D. Chen et al. / Tetrahedron Letters 50 (2009) 6944–6946
Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 1814; (d) Zou, Y.;
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.091.
5. Some reviews about aziridines: (a) Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc.
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at 40 °C. But 1a failed to react under PtCl2.
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yield if AgSbF6 was added.
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He, C. J. Am. Chem. Soc. 2004, 126, 5964; (b) Shu, X.-Z.; Liu, X.-Y.; Xiao, H.-Q.;
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while it gave 26% yield of 2a in 53 h and recover 51% 1a with H2O (0.1 mL) as
additive.
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Li, G.; Huang, X.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 6944; (c) Zhang, G.;